The goal of this proposal is to elucidate mechanisms mediating the microglia pro-inflammatory response to fibrillar beta amyloid (fAa). The interaction of microglia with Abeta plaques leads to the induction of proinflammatory signaling cascades and the release of neurotoxic secretory products. Previous studies have shown fAbeta-stimulated ROS production from the activation of microglial NADPH oxidase. The NADPH oxidase consists of the membrane associated flavoprotein cytochrome b558 and the cytosolic, p47phox, p67phox, p40phox, and Rac1. Rac must be GTP-bound to function as part of the oxidase. The cytosolic components, p47phox and p67phox, under go phosphorylation and translocation to the membrane to initiate ROS generation. Little is known about the Abeta-stimulated intracellular signaling pathways responsible for this activation. We hypothesize that fAbeta engagement of a newly discovered multireceptor cell surface complex on microglia leads to the production of ROS and subsequent neuronal damage. This proposal seeks to identify tyrosine kinase-based signaling cascades that activate intracellular signaling elements that function to stimulate assembly and activation of the NADPH oxidase following exposure to fAbeta.